Preparation of cis-fused 3,3a,8,12b-tetrahydro-2h-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan derivatives

ABSTRACT

The present invention concerns a process for preparing each of the 4 individual diastereomers of formula (I) in stereochemically pure form from a single enantiomerically pure precursor. The tetracyclic ringsystem having cis-fused five and seven membered rings is formed in a base-catalysed cyclization reaction. The invention further relates to the thus obtained cis-fused tetracyclic alcohol intermediates and methanamine end-products, and the methanamine end-products for use as a medicine, in particular as CNS active medicines.

The present invention concerns processes for the preparation of each ofthe 4 diastereomers of cis-fused3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furanderivatives in stereochemically pure form from a single enantiomericallypure precursor. The tetracyclic ring system having cis-fused five andseven membered rings is formed in a base-catalysed cyclization reaction.The invention further relates to the thus obtained cis-fused tetracyclicalcohol intermediates, the methanamine end-products, the methanamineend-products for use as a medicine, in particular as CNS activemedicines.

An article by Monkovic et al. (J. Med. Chem. (1973), 16(4), p. 403-407)describes the synthesis of(±)-3,3a,8,12b-tetrahydro-N-methyl-2H-dibenzo[3,4:6,7]-cyclohepta-[1,2-b]furan-2-methanamineoxalic acid. Said compound was synthesized as a potentialantidepressant; however, it was found that this particulartetrahydrofurfuryl-amine derivative was inactive as an antidepressant ata dose of 300 mg/kg.

WO 97/38991, published on 23 Oct. 1997, discloses tetracyclictetrahydrofuran derivatives of formula

wherein the hydrogen atoms on carbon atoms 3a and 12b have the transconfiguration. The 4 possible trans products are obtained from a racemicintermediate in a non-selective cyclization reaction and can beseparated from one another using HPLC techniques.

WO 99/19317, published on 22 Apr. 1999, concerns halogen substitutedtetracyclic tetrahydrofuran derivatives of formula

wherein the hydrogen atoms on carbon atoms 3a and 12b have the transconfiguration. The 4 possible trans products are obtained from a racemicintermediate in a non-selective cyclization reaction and can beseparated from one another using HPLC techniques.

As the method for preparing the trans-fused compounds proved ill-suitedfor upscaling, alternative routes for synthesis of these trans-fusedcompounds were explored, one of which opened a pathway to each of the 4diastereomers of the previously unknown cis-fused3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furanderivatives.

The present invention concerns a process for preparing each of the 4individual diastereomers of formula (I)

wherein the substituents on carbon atoms 3a and 12b have the cisconfiguration and the substituent on carbon atom 2 may have the R or theS configuration, comprising the step of cyclizing a compound of formula

wherein R represents C₁₋₃alkylcarbonyl;

-   -   R¹ is hydrogen and OR² is a leaving group, or    -   OR¹ is a leaving group and R² is hydrogen; and    -   the substituents R and CH₂—CHOR¹—CH₂OR² have the cis        configuration,        in a reaction inert solvent in the presence of a base, whereby        alternatively cyclizing a compound of formula        wherein R represents C₁₋₃alkylcarbonyl;    -   R¹ is hydrogen and OR² is a leaving group, or    -   OR¹ is a leaving group and R² is hydrogen; and    -   the substituents —OR and —CH₂—CHOR¹—CH₂OR² have the cis        configuration,        in a reaction inert solvent in the presence of a base, whereby

-   (ent-II-a) yields (1-d),

-   (ent-II-b) yields (1-c),

-   (ent-II-c) yields (1-b), and

-   (ent-II-d) yields (1-a).

C₁₋₃alkylcarbonyl represents methylcarbonyl, ethylcarbonyl andpropylcarbonyl; the term ‘a leaving group’ represents sulfonyloxy groupssuch as methanesulfonyloxy, trifluoromethanesulfonyloxy,benzenesulfonyloxy, 4-methylbenzenesulfonyloxy,4-nitrobenzenesulfonyloxy and 4-bromobenzenesulfonyloxy. The prefix‘ent’ designates the mirror image of the enantiomers of formula (II)shown hereinbefore.

Suitable solvents are, for example, alkanols, e.g. methanol or ethanol.Suitable bases are, for example, inorganic bases, e.g. potassiumcarbonate, particularly anhydrous potassium carbonate. The reaction canconveniently, be conducted by stirring the reagent, substrate andsolvent at ambient temperature.

Under the reaction conditions, the acyl group (OR) is saponified, thehydroxyl group on the C₃ side chain engages in a nucleophilicsubstitution reaction of the vicinal carbon atom bearing the leavinggroup forming an intermediate epoxide, and the hydroxyl on the sevenmembered ring group engages in a nucleophilic substitution reaction ofthe nearest carbon atom of the intermediate epoxide forming a cis-fusedtetrahydrofuran ring.

The numbering of the tetracyclic ring-system present in the compounds offormula (I), as defined by Chemical Abstracts nomenclature is shown informula (I′).

The compounds of formula (I) have at least three asymmetric centers,namely carbon atom 2, carbon atom 3a and carbon atom 12b. Carbon atoms3a and 12b are part of an annelated ring system. In this case, wheremore than 2 asymmetric carbon atoms are present on a ring system, thesubstituent highest in priority (according to the Cahn-Ingold-Prelogsequence rules) on the reference carbon atom, which is defined as theasymmetric carbon atom having the lowest ring number, is arbitrarilyalways in the “α” position of the mean plane determined by the ringsystem. The position of the highest priority substituent on the otherasymmetric carbon atoms relative to the position of the highest prioritysubstituent on the reference atom is denominated by “α” or “β”. “α”means that the highest priority substituent is on the same side of themean plane determined by the ring system, and “β3” means that thehighest priority substituent is on the other side of the mean planedetermined by the ring system.

The following table summarizes the nomenclatures using absolute andrelative stereodescriptors of each of the four cis-stereoisomers of thecompound of formula (I). Absolute configuration Relative configuration 23a 12b 2 3a 12b R R R α α α R S S α β β S R R α β β S S S α α α

The tetracyclic alcohols of formula (I) can be converted further intotarget compounds of pharmaceutical interest by

-   (a) converting the primary hydroxyl group into a leaving group, and-   (b) reacting the thus obtained intermediate compound of formula (IV)-    wherein R³ represents a sulfonyl group, with aqueous or gaseous    methanamine in an organic solvent at an elevated temperature, thus    yielding

A suitable organic solvent is for example tetrahydrofuran. The reactionis preferably conducted in a pressure vessel at a temperature in therange of 120° C. to 150° C.

Each of the intermediate compounds of formula

is prepared from a diol of formula

using one or more chemoselective reactions.

The intermediates of formula (II) wherein

(i) R¹ is hydrogen and OR² is a leaving group as defined hereinbefore,are prepared from the diol of formula (V) by chemoselective conversionof the primary hydroxyl group into a leaving group. One such methodcomprises stirring the diol of formula (V) in a reaction inert solventsuch as a halogenated hydrocarbon, e.g. dichloromethane, in the presenceof an excess of a base such as triethylamine, an equivalent ofdimethylaminopyridine and half an equivalent of dibutyl(oxo)stannane,and two equivalents of tosylchloride or a similar sulfonylchloride. Thereaction may also be conducted in the absence of dibutyl(oxo)stannaneand dimethylaminopyridine, but then typically will yield a mixture ofsubstrate, mono- and disubstituted product from which the desiredmono-substituted compound needs to be separated.

Or, the intermediates of formula (II) wherein

(ii) OR¹ is a leaving group and R² is hydrogen, are prepared from thediol of formula (V) by

-   -   (1) chemoselective protection of the primary hydroxyl group with        an acid labile protecting group such as a trityl group;    -   (2) converting the secondary hydroxyl group into a leaving group        by reaction with a sulfonylchloride in a solution of        dichloromethane in the presence of triethylamine and        diethylaminopyridine;    -   (3) deprotecting the primary hydroxyl group in the thus obtained        intermediate of formula (VI)        wherein Tr represents trityl, in the presence of an acid such as        an acidic ion exchange resin, e.g. Amberlyst-15, in a reaction        inert solvent such as an alkanol e.g. methanol, at a temperature        ranging from 40° C. to 60° C.

The overall reaction scheme for converting diol (V) into intermediateII-b thus is as follows

The intermediate diol of formula (V) can be prepared from a ketone offormula

by the following series of reaction steps:

-   (a) reducing the ketone of formula (VII) to the cis-oriented    hydroxyl group by reaction with lithium or sodium borohydride in a    mixture of an organic solvent and an aqueous buffer having a pH of    about 7 at a temperature below ambient temperature;-   (b) acylating the hydroxyl group with an acylchloride or acyl    anhydride following art-known procedures, and-   (c) unmasking the diol by a deacetalisation reaction in an organic    solvent in the presence of an acid, whereby

The intermediate ketones of formula (VII) are prepared from theα,β-unsaturated ketone (VIII)

by either Pd/C catalyzed hydrogenation or a reduction procedure usingsodiumcyanoborohydride, yielding a mixture of epimeric ketones (VII-a)and (VII-b) in a rather invariant ratio of about 3:2.

The hydrogenation reaction may conveniently be conducted in a variety ofsolvents such as alcohols, e.g. methanol, ethanol, isopropanol; esters,e.g. ethyl acetate; ethers, e.g. tetrahydrofuran; aromatic hydrocarbons,e.g. toluene; optionally in the presence of a tertiary amine such astriethylamine or quinine.

Reduction of (VIII) can be accomplished with sodium cyanoborohydrideunder slightly acidic conditions.

The epimeric ketones (VII-a) and (VII-b) can be obtained separately bychromatographic separation (diethylether/hexane 60/40). Separation canalso be effected on the epimeric alcohols obtained following reductionof (VII) according to step (a).

To prepare intermediate (VIII),(4S)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde (IX) and pro-chiralketone (X) can be dissolved in a suitable solvent such astetrahydrofuran and treated with a base such as tert.butyloxypotassiumsalt and a co-reagent such as magnesium chloride or bromide (aldolcondensation).

The pro-chiral ketone (X) can be prepared by adaption of an art-knownsequence (Can. J. Chem., 1971, 49, 746-754) starting with aFriedel-Crafts acylation reaction using fluorobenzene and phthalicanhydride to form keto-acid (XI), followed by reductive removal of theketone group and homologation of the carboxylic acid function.

Cyclization of the homologous acid (XII) in another Friedel-Craftsacylation affords ketone (X).

The process according to the present invention provides anenantioselective approach to the target molecule (III) in enantiopureform via the enantiopure alcohols of formula (I). Both target andintermediate molecules of formulae (III) and (I) are novel.

The pharmaceutically active compounds of formula (III) may occur intheir free form as a base or in a pharmaceutically acceptable salt formobtained by treatment of the free base with an appropriate non-toxicacid such as an inorganic acid, for example, hydrohalic acid, e.g.hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the likeacids; or an organic acid, such as, for example, acetic, hydroxyacetic,propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric,malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

The term ‘enantiopure form’ designates compounds and intermediateshaving a stereoisomeric excess of at least 80% (i.e. minimum 90% of oneisomer and maximum 10% of the other possible isomers) up to astereoisomeric excess of 100% (i.e. 100% of one isomer and none of theother), more in particular, compounds or intermediates having astereoisomeric excess of 90% up to 100%, even more in particular havinga stereoisomeric excess of 94% up to 100% and most in particular havinga stereoisomeric excess of 97% up to 100%.

The compounds of the present invention show affinity for 5-HT receptors,particularly for 5-HT_(2A), 5-HT_(2C) and 5-HT₇ receptors (nomenclatureas described by D. Hoyer in “Serotonin (5-HT) in neurologic andpsychiatric disorders” edited by M. D. Ferrari and published in 1994 bythe Boerhaave Commission of the University of Leiden). The serotoninantagonistic properties of the present compounds may be demonstrated bytheir inhibitory effect in the “S-hydroxytryptophan Test on Rats” whichis described in Drug Dev. Res., 13, 237-244 (1988). Furthermore, thecompounds of the present invention show interesting affinity forH₁-receptors (pIC₅₀: 7.15-7.89), D2 and/or D3 receptors, andsurprisingly for norepinephrine reuptake transporters (pIC₅₀:6.03-7.34).

In view of these pharmacological and physicochemical properties, thecompounds of formula (III are useful as therapeutic agents in thetreatment or the prevention of central nervous system disorders likeanxiety, depression and mild depression, bipolar disorders, sleep- andsexual disorders, psychosis, borderline psychosis, schizophrenia,migraine, personality disorders or obsessive-compulsive disorders,social phobias or panic attacks, organic mental disorders, mentaldisorders in children, aggression, memory disorders and attitudedisorders in older people, addiction, obesity, bulimia and similardisorders. In particular, the present compounds may be used asanxiolytics, antipsychotics, antidepressants, anti-migraine agents andas agents having the potential to overrule the addictive properties ofdrugs of abuse.

The compounds of formula (III) may also be used as therapeutic agents inthe treatment of motoric disorders. It may be advantageous to use thepresent compounds in combination with classical therapeutic agents forsuch disorders.

The compounds of formula (III) may also serve in the treatment or theprevention of damage to the nervous system caused by trauma, stroke,neurodegenerative illnesses and the like; cardiovascular disorders likehigh blood pressure, thrombosis, stroke, and the like; andgastrointestinal disorders like dysfunction of the motility of thegastrointestinal system and the like.

In view of the above uses of the compounds of formula (III), it followsthat the present invention also provides a method of treatingwarm-blooded animals suffering from such diseases, said methodcomprising the systemic administration of a therapeutic amount of acompound of formula (III) effective in treating the above describeddisorders, in particular, in treating anxiety, psychosis, schizophrenia,depression, migraine, sleep disorders and addictive properties of drugsof abuse.

The present invention thus also relates to compounds of formula (III) asdefined hereinabove for use as a medicine, in particular, the compoundsof formula (III) may be used for the manufacture of a medicament fortreating anxiety, psychosis, schizophrenia, depression, migraine, sleepdisorders and addictive properties of drugs of abuse.

Those of skill in the treatment of such diseases could determine theeffective therapeutic daily amount from the test results presentedhereinafter. An effective therapeutic daily amount would be from about0.01 mg/kg to about 10 mg/kg body weight, more preferably from about0.05 mg/kg to about 1 mg/kg body weight.

For ease of administration, the subject compounds may be formulated intovarious pharmaceutical forms for administration purposes. To prepare thepharmaceutical compositions of this invention, a therapeuticallyeffective amount of the particular compound, optionally in addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which may take a wide variety offorms depending on the form of preparation desired for administration.These pharmaceutical compositions are desirably in unitary dosage formsuitable, preferably, for administration orally, rectally,percutaneously, or by parenteral injection. For example, in preparingthe compositions in oral dosage form, any of the usual pharmaceuticalmedia may be employed, such as, for example, water, glycols, oils,alcohols and the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable solutions containing compoundsof formula (III) may be formulated in an oil for prolonged action.Appropriate oils for this purpose are, for example, peanut oil, sesameoil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol estersof long chain fatty acids and mixtures of these and other oils.Injectable suspensions may also be prepared in which case appropriateliquid carriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewettable agent, optionally combined with suitable additives of anynature in minor proportions, which additives do not cause anysignificant deleterious effects on the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as a spot-onor as an ointment. Acid or base addition salts of compounds of formula(III) due to their increased water solubility over the correspondingbase or acid form, are more suitable in the preparation of aqueouscompositions.

In order to enhance the solubility and/or the stability of the compoundsof formula (III) in pharmaceutical compositions, it can be advantageousto employ α-, β- or γ-cyclodextrins or their derivatives, in particularhydroxyalkyl substituted cyclodextrins, e.g.2-hydroxypropyl-o-cyclodextrin. Also co-solvents such as alcohols mayimprove the solubility and/or the stability of the compounds of formula(III) in pharmaceutical compositions.

Other convenient ways to enhance the solubility of the compounds of thepresent invention in pharmaceutical compositions are described in WO97/44014.

More in particular, the present compounds may be formulated in apharmaceutical composition comprising a therapeutically effective amountof particles consisting of a solid dispersion comprising a compound offormula (III), and one or more pharmaceutically acceptable water-solublepolymers.

The term “a solid dispersion” defines a system in a solid state (asopposed to a liquid or gaseous state) comprising at least twocomponents, wherein one component is dispersed more or less evenlythroughout the other component or components. When said dispersion ofthe components is such that the system is chemically and physicallyuniform or homogenous throughout or consists of one phase as defined inthermodynamics, such a solid dispersion is referred to as “a solidsolution”. Solid solutions are preferred physical systems because thecomponents therein are usually readily bioavailable to the organisms towhich they are administered.

The term “a solid dispersion” also comprises dispersions which are lesshomogenous throughout than solid solutions. Such dispersions are notchemically and physically uniform throughout or comprise more than onephase.

The water-soluble polymer in the particles is a polymer that has anapparent viscosity of 1 to 100 mPa.s when dissolved in a 2% aqueoussolution at 20° C. solution.

Preferred water-soluble polymers are hydroxypropyl methylcelluloses orHPMC. HPMC having a methoxy degree of substitution from about 0.8 toabout 2.5 and a hydroxypropyl molar substitution from about 0.05 toabout 3.0 are generally water-soluble. Methoxy degree of substitutionrefers to the average number of methyl ether groups present peranhydroglucose unit of the cellulose molecule. Hydroxy-propyl molarsubstitution refers to the average number of moles of propylene oxidewhich have reacted with each anhydroglucose unit of the cellulosemolecule.

The particles as defined hereinabove can be prepared by first preparinga solid dispersion of the components, and then optionally grinding ormilling that dispersion. Various techniques exist for preparing soliddispersions including melt-extrusion, spray-drying andsolution-evaporation, melt-extrusion being preferred.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Experimental Part

Hereinafter, “DMF” is defined as N,N-dimethylformamide, “THF” is definedas tetrahydrofuran, “DIPE” is defined as diisopropyl ether, “HCl_(cp)”is defined as chemically pure hydrochloric acid (34.5% w/w).

A. Preparation of the Intermediate Compounds

EXAMPLE A1a

Intermediate 1: 2-(4-fluorobenzoyl)benzoic acid —CAS RN [7649-29-5] (i)A solution of p-fluorobenzenemagnesium bromide (1.2M solution in THF, 1eq.) was added to a 0.4M solution of phthalic anhydride in THF, so thatthe temperature remained under 30° C. After 1 h, half of the solvent wasdistilled off and the reaction mixture was stirred overnight at roomtemperature. The obtained precipitate was filtered off and taken up inwater (0.3 L/mol). Toluene (1 L/mol) and HCl_(cp) were added so that thetemperature remained under 35° C. After stirring 1 h, the organic layerwas evaporated (50° C., vac.) and the obtained solid was dried at 50° C.under vacuum.

Physical yield: 74%

Purity: 93% (LC abs %)

Active yield: 69% of intermediate 1

(ii) Alternatively, a Friedel-Crafts reaction can be performed:

Phthalic anhydride, fluorobenzene (1.2 eq.) and CH₂Cl₂ (0.5 L/mol) weremixed at room temperature. AlCl₃ (0.8 eq.) was added over 60 min. (at 1mol scale). After 5 h at room temperature, the mixture was heated up toreflux during 18 h, then cooled down to room temperature and poured veryslowly in ice/water and stirred during 1 h. The organic layer wasseparated and the water layer was extracted with CH₂Cl₂ (0.25 L/mol) Thecombined organic layers were washed with water (0.3 L/mol), thenextracted with 320 ml water (0.7 L/mol)/NaOH 50% (0.07 L/mol). The waterlayer was separated and washed with 60 ml CH₂Cl₂ (0.15 L/mol)Norit-A-Supra (active charcoal) (10 g/mol) was added and the mixture wasstirred and filtered.

Water (0.7 L/mol)/HCl_(cp) (2.5 eq.) solution was added dropwise, themixture was stirred during 30 min., the precipitate filtered off, washedwith water (2×0.2 L/mol) and dried.

Yield: 92% of intermediate 1.

EXAMPLE A1b

Intermediate 2: 2-[(4-fluorophenyl)methyl]benzoic acid-CAS RN [346474]

Intermediate 1 was dissolved in isopropanol (2 L/mot) and Pd/C (10% dry)was added. The reaction mixture was heated up to 45° C. and hydrogenatedovernight at atmospheric pressure. After cooling the flask to roomtemperature, the catalyst was filtered off over diatomaceous earth andrinsed with 30 ml isopropanol. The filtrate was evaporated at 45° C.under vacuum.

Physical yield: 98%

Purity: 96.4% (LC abs %)

Active yield: 94% of intermediate 2

EXAMPLE A1c

Preparation of intermediate 3

Intermediate 2 was dissolved in toluene (1.5 L/mol) and DMF (1 ml/mol)was added. The reaction mixture was heated up to 40° C. and thionylchloride (1.1 eq.) was added. During the addition the reaction mixturewas further heated up to 50° C. The reaction mixture was stirred at 50°C. during 2 h 30, then evaporated at 50° C. under vacuum. THF (0.3L/mol) was added and that solution was dropped into a 2M NaBH₄ solutionin THF (1.5 eq.). The temperature rose to reflux (67° C.) and thereaction mixture was stirred at reflux during 2 h. The reaction mixturewas cooled down to room temperature. Aceton (350 ml/mol) was added(temperature rose to 40° C.), the reaction mixture was stirred during 30minutes, followed by toluene (1 L/mol) and water (1.5 L/mol). Thereaction mixture was heated up to 50° C. and the organic layerevaporated at 50° C. under vacuum. CH₂Cl₂ (3 L/mol) was added, followedby triethylamine (1.1 eq.). SOCl₂ (1.1 eq.) was added dropwise, thetemperature rose to reflux. The reaction mixture was stirred during 45min to room temperature. Water (1 L/mol) was added and the reactionmixture was stirred vigorously during 15 min. The organic layer waswashed a second time with water (1 L/mol) and evaporated (40° C., vac.).The product was dissolved in toluene (2.5 L/mol), tetrabutylammoniumhydrogenosulfate (phase-transfer reagent) (0.1 eq.) was added at 70° C.NaCN 6M (1.6 eq.) was added at 70° C. under vigorous stirring. Thereaction mixture was then heated up to reflux and stirred 3 h. Aftercooling down to room temperature, water (0.5 L/mol) was added, thereaction mixture was stirred during 30 minutes. After washing a secondtime with water (0.5 L/mol), drying on MgSO₄ and evaporating thesolvent, intermediate 3 was obtained.

Physical yield: 98%

Purity: 96.4% (LC abs %)

Active yield: 94% of intermediate 3

EXAMPLE A1d

Preparation of Intermediate 4

Intermediate 3 was suspended in acetic acid (0.5 L/mol), water (0.3L/mol) and sulfuric acid (0.35 L/mol). After 5 h at reflux, the mixturewas cooled down, water (1.2 L/mol) and dichloromethane (0.3 L/mol) wereadded. The organic extract was washed with water (1.3 L/mol) and NaOH50% (0.15 L/mol). After stirring 20 min., the aqueous layer wasseparated and washed with CH₂Cl₂ (0.1 L/mol), which was discarded. Theaqueous layer was acidified with HCl_(cp) (2 eq.). The mixture wasstirred during 3 h, the precipitate was then filtered off and washedwith water (0.1 L/mol).

Yield: 74% of intermediate 4

EXAMPLE A1e

Preparation of Intermediate 5

Intermediate 4 was dissolved in dichloromethane (0.6 L/mol) andN,N-dimethyl acetamide, 15 ml/mol). Thionyl chloride (1 eq.) was addeddropwise and the reaction mixture was refluxed during 1 h30. Aftercooling down to 0° C., AlCl₃ (1 eq.) was added and the mixture wasstirred during 2 h. HCl, (2 eq.) and water (0.3 L/mol) were added. Thelayers were separated, the organic layer was washed with 5% NaHCO₃solution (0.6 L/mol), then with water. The organic layer was evaporated,isopropanol (0.25 L/mol) was added. The mixture was heated up to reflux(30 min.) and cooled down. Seeding occured at 65° C. After cooling downfurther and stirring 2 h at rt, the precipitate was filtered off, washedwith isopropanol (0.05 L/mol) and dried at 50° C. under vacuum.

Yield: 40-80% of intermediate 5.

Typical purity between 77% and 93%

EXAMPLE A1f

Preparation of Intermediate 6

Intermediate 5 was dissolved in toluene (2 L/mol). MgCl₂ anhydrous (1.2eq.) was added and the reaction mixture was stirred at room temperatureduring 30 min. (S)-solketal aldehyde (from DSM, 1.7 eq., 20% solution inTHF) was added and in one time 0.2 eq. potassium tert-butoxide. Slightexothermicity was observed. The reaction mixture was stirred during 68 hat room temperature. Water (0.5 L/mol) was added, followed by 0.2 eq.HCl_(cp). The reaction mixture was stirred vigorously during 5 min. Theorganic layer was washed again with 0.5 L/mol water, then again with 1L/mol water. After adding Na₂SO₄ (125 g/mol), active carbon (40 g/mol),the mixture was filtered, the remaining solid was rinsed with toluene(0.2 L/mol) and the filtrate was evaporated. Isopropanol (1.5 L/mol) wasadded, the reaction mixture was stirred at least 8 h at 20-25° C., thencooled down to 0-5° C. and stirred at that temperature for at least 2 h.The precipitate was filtered off, washed with cold isopropanol (0.07L/mol) and air-dried at 40° C.

Physical yield: 58%

Purity: 93.1% (LC abs %)

Active yield: 54% of intermediate 6.

The product could be recrystallized from iPrOH.

EXAMPLE A1g

Preparation of Intermediate 7

Intermediate 6 was dissolved in acetone (2 L/mol), triethylamine (1 eq.)and thiophene (4% solution in EtOH, 0.007 L/mol.) were added. Aftersuspending Pd/C (60 g/mol, 10% wet), the hydrogenation was performed. Incase the conversion was low, another 60 g/mol Pd/C was added and thehydrogenation was continued till complete conversion. Some exothermicitywas observed (temperature rises to 35° C.). When the reaction wascompleted, the catalyst was filtered off over diatomaceous earth and thesolid was rinsed with acetone (0.07 L/mol). The filtrate was evaporated(atm.) at 75-80° C. The residue was cooled down to 70-75° C. Isopropanolwas added (0.84 L/mol), then evaporated again. The reaction mixture wascooled down. At 45-50° C., triethylamine (1 eq.) was added to theheterogeneous mixture. After stirring at least 8 h at 45-50° C., themixture was cooled down to 20-25° C., stirred 2-16 h at 20-25° C.,cooled down to 0-5° C. and stirred at that temperature during 2-16 h.The precipitate was filtered off, washed with cold isopropanol (0.07L/mol) and dried during 16 h at 50° C. under vacuum. A light rose solidwas obtained.

Physical yield: 83% of intermediate 7.

EXAMPLE A2a

Preparation of Intermediate 8

In THF (1.4 L/mol), a buffer solution of pH 7 containing potassiumdihydrogenphosphate and disodium hydrogenphosphate, 0.3 L/mol was added.The mixture was cooled down to 0-5° C. and intermediate 7 was added.Lithium borohydride 2N in THF (0.48 eq.) was added and the temperaturewas maintained under 10° C. After the addition, the reaction mixture wasstirred during 2 h at 0-5° C. Acetone (1.7 eq.) was is cautiously addedand the reaction mixture was stirred to room temperature. Water (0.7L/mol) was added at 10-25° C. and the reaction mixture was stirred 30min. at room temperature. Acetic acid (2.2 eq.) and 200 ml toluene wereadded. After stirring during 10 min., the organic layer was washed withwater (0.36 L/mol) and NaOH 50% (2.2 eq.), then washed again twice withwater (0.45 L/mol). The solution was evaporated (a viscous oil wasobtained) and dichloromethane (1 L/mol) was added. The solution was usedfurther in the next step, assuming that 100% intermediate 8 had beenobtained.

EXAMPLE A2b

Preparation of Intermediate 9

Dimethylaminopyridine (0.05 eq.) and triethylamine (1.1 eq.) were addedto intermediate 8 (solution in CH₂Cl₂). Acetic anhydride (1.1 eq.) wasadded dropwise. The temperature was allowed to rise to 40° C. Thereaction mixture was stirred during 2 h and NH₄Cl 1N (0.5 eq.). About90% of the solvent was distilled off (atmospheric pressure) andisopropanol (1 L/mol) was added. About one fifth of the solvent wasevaporated (atmospheric pressure) and the reaction mixture was slowlycooled down to room temperature and stirred overnight. After coolingdown further to 0-5° C. and stirring at that temperature during 8-16 h,the precipitate was filtered off and washed with isopropanol (0.2L/mol). The product was dried for 16 h at 50° C. under vacuum.

Active yield: 80% of intermediate 9.

EXAMPLE A2c

Preparation of Intermediate 10

Intermediate 9 was suspended in water (0.3 L/mol) and glacial aceticacid (0.45 L/mol) was added. This mixture was stirred at 55° C. for 8hours. The reaction proceeded to 93% conversion. The reaction mixturewas cooled to ambient temperature. Water (1.5 L/mol) and methylenechloride (0.8 L/mol) were charged and the mixture was stirred for 15minutes. The water phase was separated and extracted three times withmethylene chloride (each time with 0.6 L/mol). The combined organicphases were washed with water (1 L/mol) and dried over sodium sulfate.The solvent was evaporated, yielding a fluffy white solid.

Active yield: 94% of intermediate 10.

EXAMPLE A2d

Preparation of intermediate 11

Intermediate 10 was dissolved in toluene (3.5 L/mol) andp-toluenesulfonyl chloride (1.5 eq.) was added in one portion. To thismixture, pyridine (10 eq.) was added dropwise. The reaction mixture wasstirred 4 h at 40° C. Water (1.5 L/mol) was added, followed by 1 Mammonium chloride (1.3 eq.). After drying the organic phase over sodiumsulfate, the organic solvent was evaporated yielding crude product,which was a mixture of starting material (8%), mono-tosylate (76%) anddi-tosylate (16%) (LC area %).

Yield: 61% of intermediate 11.

EXAMPLE A2e

Preparation of intermediate 12

To a solution of intermediate 11 (0.62 g, 1.23 mmol) in MeOH (30 mL) wasadded K₂CO₃ (0.34 g, 2.46 mmol) and the mixture was stirred at roomtemperature for 1 day. 25 mL NH₄Cl (sat. aq. solution) was added,extracted 3 times with CH₂Cl₂ (3×20 mL) and then dried on MgSO₄. Columnpurification on silica gel using ether/hexane (70:30) gave intermediate12 as a white crystalline product (0.32 g, 90%) (mp. 157-158° C.).

EXAMPLE A2f

Preparation of intermediate 13

Intermediate 12 (0.31 g, 1.09 mmol) in CH₂Cl₂ was dissolved. Et₃N (0.46ml, 3.28 mmol), DMAP (64 mg, 0.55 mmol) and TsCl (0.32 g, 1.64 mmol)were added. The solution was stirred at room temperature for 3 hr. NH₄Cl(sat. aq. sol.) was added and the aqueous layer was extracted 3 timeswith CH₂Cl₂ and dried with magnesium sulfate. Column purification onsilica gel with Ether/Hexane (60/40) gave an yellowish oil. Yield: 0.46g of intermediate 13 [(2S, 3aR,12bR)-11-fluoro-3,3a,8-12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-2-yl]methyl4-methylbenzenesulfonate (96%).

EXAMPLE A3

Preparation of Intermediate 14

Acetate diol (intermediate 10) (826 mg, 2.39 mmol) was dissolved inCH₂Cl₂ (12 ml). Et₃N (4 ml) and Ph₃CCl (1.50 g, 5.38 mmol) were addedand stirred at room temperature for 6 hr. NH₄Cl (sat. aq. sol.) wasadded. The mixture was extracted 3 times with CH₂Cl₂ and dried withMgSO₄. The solution was evaporated. Column purification on silica gelusing ether/hexane (40/60) gave an oil (0.95 g, 68%). The above oil wasdissolved in CH₂Cl₂, Et₃N (2.2 ml, 1.58 mmol), DMAP (190 mg, 1.56-mmol)and MsCl (190 μl 2.45 mmol) were added. The reaction mixture was stirredat room temperature for 2 hr. NH₄Cl (sat. aq. sol.) was added, themixture was extracted 3 times with CH₂Cl₂ and dried with MgSO₄. Columnpurification on silica gel by using ether/hexane (40/60) gave an oil(900 mg, 84%). This oil (840 mg, 1.26 mmol) was dissolved in MeOH (25ml), Amberlyst (4.5 g) was added and heated at 50° C. for 3 hr. TheAmberlyst was filtered off and evaporated. The remaining oil wasdissolved in MeOH (15 ml) and K₂CO₃ (1.68 g, 10.0 mmol) was added. Thereaction mixture was stirred at room temperature for 18 hr. NH₄Cl wasadded and extracted 3 times with CH₂Cl₂ and dried with MgSO₄. Columnpurification on silica gel by using ether gave a white crystallinecompound (Yielding: 330 mg of intermediate 14 [(2R, 3aR,12bR)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-2-yl]methanol,92%).

Table 1 lists the intermediates that were prepared according to one ofthe above Examples. TABLE 1 Int. Ex. No. No. Structure Physical data 1A2f

2S, 3aR, 12bR; mp.: 157-158° C. 2 A3

2R, 3aR, 12bR; mp. 99-101° C. 3 A3

2R, 3aS, 12bS; ¹H NMR: 1.90(br s, 1H, OH), 2.05 (ddd, 1H, J=12.6, 9.6,8.4Hz, CH₂- 3), 2.48(ddd, 1H, J=12.6, 8.4, 3.6 Hz, CH ² ′-3),3.70-3.80(m, 2H, CH₂OH), 3.81(d, 1H, J=14.2Hz, CH₂-8), 3.94(q, 1H,J≅8.1Hz, CH- 3a), # 4.04(d, 1H, J=14.4Hz, CH₂′- 8), 4.48(m, 1H, CH-2),5.62(d, 1H, J=8.1Hz, CH-12b), 6.84(dt, 1H, J=2.6, 8.2Hz, Ar—H-10),6.87(dd, 1H, J=8.1, 2.7Hz, Ar—H-4), 7.07-7.20(m, 5H, Ar—H). 4 A2f

2S, 3aS, 12bS; ¹H NMR: 2.02(br s, 1H, OH), 2.02-2.12(m, 1H, CH₂-3),2.49(ddd, 1H, J=12.9, 8.0, 3.9Hz, CH₂′-3), 3.67-3.76(m, 1H, CH ² —OH),3.78-3.86(m, 1H, CH ² ′—OH), 3.83(d, 1H, J=14.1 Hz, CH₂-8), 3.94(q, 1HJ≅8.8 Hz, CH-3a), 4.05(d, 1H, # J=14.1 Hz, CH₂′-8), 4.45-4.54(m, 1H,CH-2), 5.63(d, 1H, J=7.3Hz, CH-12b), 6.84(dt, 1H, J=2.9, 8.4Hz, Ar—H-10), 7.08-7.20(m, 6H, Ar—H).B. Preparation of the Final Compounds

EXAMPLE B1

Preparation of Compound 1

The tosylated compound (intermediate 13) (0.46 g, 1.05 mmol) wasdissolved in THF (15 ml) and 40% CH₃NH₂ solution (15 ml) was added. Thereaction mixture was brought into a tightly sealed steel vessel andheated at 130° C. for 12 hr. The mixture was cooled down to roomtemperature and NH₄Cl (sat. aq. sol.) was added. The solution wasextracted 3 times with CH₂Cl₂ and dried with MgSO₄. After evaporation,the residue was purified on silica gel column with MeOH/CHCl₃ (15/85) togive an yellowish oil (Yield: 0.30 g, 97% of compound 1[(2S,3aR,12bR)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-2-yl]-N-methylmethanamine).

EXAMPLE B2

Preparation of Compound 2

To a solution of alcohol (intermediate 14) (172 mg, 0.605 mmol) inCH₂Cl₂(15 mL) was added TsCl (0.20 g, 1.05 mmol), Et₃N (0.25 mL, 1.80mmol), DMAP (37 mg, 0.303 mmol). The reaction mixture was stirred atroom temperature for 2 hr. 15 mL NH₄Cl (sat. aq. solution) was added.The mixture was extracted 3 times with CH₂Cl₂ (3×15 mL) and dried withMgSO₄. Column purification on silica gel by using ether/Hexane (60:40)gave an oil (0.26 g, 95%). To this oil (0.26 g, 0.571 mmol) in THF (15mL) was added 40% MeNH₂ aqueous solution (15 mL). This solution was putinto a tightly sealed steel vessel and heated at 130° C. for 12 hr.After cooling down to room temperature 15 mL NH₄Cl (sat. aq. solution)was added. The solution was extracted 3 times with CH₂Cl₂ (3×15 mL) anddried with MgSO₄. Column purification on silica gel using MeOH/CHCl₃(15:85) yielded a yellow solid (Yielding: 0.16 g, 94% of compound 2[(2R,3aR,12bR)-11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-2-yl]-N-methylmethanamine).

Table 2 lists the compounds that were prepared according to one of theabove Examples. TABLE 2 Comp Ex. No. No. Structure Physical data 1 B1

2S, 3aR, 12bR: Mass spectrum: CI m/z(assignment, relative intensity) 298(MH⁺, 100%) EI: m/z(assignment, relative intensity) 297(M⁺, 12%),209(100%) High resolution EI Calculated C₁₉H₂₀FNO(M⁺): 297.1529 Found:297.1526(56%) 2 B2

2R, 3aR, 12bR; mp. 214-215° C. 3 B2

2R, 3aS, 12bS; ¹HNMR: 2.11(ddd, 1H, J=12.5, 10.0, 8.7 Hz, CH₂-3),2.41(ddd, 1H, J=12.5, 8.7, 3.8 Hz, CH₂′-3), 2.50(br s, 1H, NH), 2.58(s,3H, CH₃) 2.78-2.96(m, 2H, CH ² NHMe), 3.79(d, 1H, J=14.6Hz, CH₂-8),3.90(q, 1H, # J≅8.6 Hz, CH-3a), 3.99(d, 1H, J=14.6Hz, CH₂′- 8),4.41-4.51(m, 1H, CH-2), 5.57(d, 1H, J=7.5Hz, CH-12b), 6.80(dt, 1H,J=2.5, 8.4 Hz, Ar—H-b), 7.06 4 B1

2S, 3aS, 12bS; ¹H NMR: 2.06-2.16(m, 1H, CH₂-3), 2.29(s, 1H, NH),2.40(ddd, 1H, J=12.6, 7.9, 3.6Hz, CH₂′-3), 2.54(s, 3H, CH₃),2.72-2.90(m, 2H, CH ² NHMe), 3.82(d, 1H, J=14.3Hz, CH₂- 8), 3.91(q, 1H,J≅8.3Hz, CH-3a), 4.02(d, 1H, J=14.3Hz, CH₂′-8), 4.48- # 4.58(m, 1H,CH-2), 5.57(d, 1H, J=7.3Hz, CH-12b), 6.82(dt, 1H, J=2.8, 8.3Hz,Ar—H-10), 7.06-7.20 (m, 6H, Ar—H)

1. A process for preparing each individual diastereoisomer of formula(I):

wherein the substituents on carbon atoms 3a and 12b have the cisconfiguration, the substituent on carbon atom 2 may have the R or the Sconfiguration, comprising the step of cyclizing a compound of formula(II)

wherein R represents C₁₋₃ alkylcarbonyl; R¹ is hydrogen and OR² is aleaving group, or OR¹ is a leaving group and R² is hydrogen; and thesubstituents —OR and —CH₂—CHOR¹—CH₂OR² have the cis configuration, in areaction inert solvent in the presence of a base, whereby

alternatively cyclizing a compound of formula

wherein R represents C₁₋₃alkylcarbonyl; R¹ is hydrogen and OR² is aleaving group, or OR¹ is a leaving group and R² is hydrogen; and thesubstituents —OR and —CH₂—CHOR¹—CH₂OR² have the cis configuration, in areaction inert solvent in the presence of a base, whereby (ent-II-a)yields (1-d), (ent-II-b) yields (1-c), (ent-II-c) yields (1-b), and(ent-II-d) yields (1-a).
 2. A process according to claim 1 wherein eachindividual diastereomer of formula (I) is converted further into atarget compound of formula (III) comprising the further steps of (a)converting the primary hydroxyl group into a leaving group, and (b)reacting the thus obtained intermediate compound of formula

 wherein R³ represents a sulfonyl group with aqueous methylamine in anorganic solvent at an elevated temperature, thus yielding


3. A process according to claim 1 wherein the compound of formula (II)

(i) wherein R¹ is hydrogen and OR² is a leaving group and thesubstituents —OR and —CH₂—CHOR¹—CH₂—OR² have the cis configuration isprepared from a diol of formula

 wherein the substituents —OR and —CH₂—CHOH—CH₂—OH have the cisconfiguration, by selective conversion of the primary hydroxyl groupinto a leaving group, or (ii) wherein OR¹ is a leaving group and R² ishydrogen and the substituents —OR and —CH₂—CHOR¹—CH₂—OR² have the cisconfiguration is prepared from a diol of formula

 wherein the substituents —OR and —CH₂—CHOH—CH₂—OH have the cisconfiguration by 1) selective protection of the primary hydroxyl groupwith an acid labile protecting group, 2) conversion of the secondaryhydroxyl group into a leaving group, and 3) deprotection of the primaryhydroxyl group by treatment with an acid.
 4. A process according toclaim 3 wherein the intermediate diol of formula (V)

wherein the substituents have the cis configuration is prepared from aketone of formula (VII)

 by the following series of reaction steps (a) reduction of the ketoneto the cis-oriented hydroxyl group by reaction with lithium or sodiumborohydride in a mixture of an organic solvent and an aqueous bufferhaving a pH of about 7 at a temperature below ambient temperature; (b)acylation of the hydroxyl group following art-known procedures; and (c)deacetalisation in an organic solvent in the presence of an acid,whereby


5. A process according to claim 4 wherein the ketone of formula (VII)

is prepared from a pro-chiral ketone of formula (X) and(4S)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde (IX) in an aldolreaction,

yielding unsaturated ketone (VIII) and reducing said unsaturated ketoneto a mixture of epimeric ketones (VII-a) and (VII-b).
 6. An intermediatecompound of formula (I) having the formula


7. A compound of formula (III) having the formula

in free base form or a pharmaceutically acceptable acid addition saltform thereof.
 8. A compound of formula (III) according to claim 7 foruse as a medicine.
 9. A compound according to claim 8 for use as a CNSactive medicine.
 10. A pharmaceutical composition comprising apharmaceutically effective amount of a compound of formula (III) asdefined in claim 7 and a pharmaceutically acceptable carrier.